Certificate of correction



tates Bill Elpern, Delmar, N. Y., assignor to Sterling Drug Inc., NewYork, N. Y., a corporation of Delaware No Drawing. Application September12, 1955 Serial No. 533,894

14 Claims. (Cl. 260-2943) This invention relates to organic compoundsand their preparation, and is concerned with an improvement in thesubstituent attached to the nitrogen atom of the piperidine ring in theclass of chemical compounds identlfied as lower alkyl4phenyl-1-(hydrocarbyDpiperidine- 4-carboxylates. In particular, it isconcerned with lower alkyl 4-phenyl-1-(3-phenyl-alkenyl and-alkynyl)piperidine-4-carboxylates, their acid addition salts, and thepreparation of these compounds.

Attempts have been made for some time to develop analgesics having highactivity. The highly potent morphine has the disadvantages of causingnausea, vomiting, constipation, and resipratory depression, and forthese reasons has been supplanted largely by meperidine, ethyl4-phenyl-l-methylpiperidine-4-carboxylate, especially in obstetricswhere depression of respiration is highly undesirable. Because of therelatively high dose required, meperidine has to be injected inhypertonic concentrations, with a consequent risk of irritation at thesite of administration. This limits the choice of concentrations whichcan be used 'and restricts undesirably the free choice of optimumdosage. This situation is advantageously modified with the compounds ofmy invention since they are many times more potent as analgesics thanmeperidine and thus can be administered in smaller volumes of solutionand at higher therapeutic levels of effectiveness without making thesolution hypertonic. This reduces any tendency to undesirableaccompanying irirtation, and improves the therapeutic usefulness of themedicament.

U. S. Patent 2,167,351 broadly shows lower alkyl 4-aryl-l-(substituted)piperidine-4-carboxylates where the l-substituent isa monovalent hydrocarbon radical. Ineluded among the specific examplesare such compounds having l-methyl and l-benzyl substituents, the latterbeing of primary value as intermediates for the former. The l-methylcompounds are not known and accepted as eifective, morphine-like centralanalgesics and atropinelike smooth muscle neurospasmolytics in therelief of severe pain. An outstanding example of these l-methylcompounds is the commercially available meperdine hydrochloride, ethyl4-phenyl-1-methylpiperidine-4-carboxylate hydrochloride. On the otherhand, the intermediate l-benzyl compounds have been found to have adecidedly lower analgesic activity compared with the l-methyl compounds.For example, ethyl 4-phenyl-1- benzylpiperidine-4-carboxylate as itshydrochloride has been found to be only approximately one-fourth asefiective an analgesic as meperidine hydrochloride when tested by theBass-lander Brook modification of the DAmour- Smith method. Thisdecrease in activity in going from l-methyl to l-benzyl would indicatethat l-phenylalkyl substituents are undesirable, and would thus leadinvestigators away from these compounds and away from compounds such asthose of my. invention. A

I have now prepared lower alkyl 4-phenyl-l-(3-phenylalkenyl and-a1kynyl)piperidine-4-carboxylates and sur prisingly found them to beoutstandingly superior as analatent 2,824,875 Patented Feb. 25, 1958gesics compared with the corresponding 1-benzyl compounds of U. S.Patent 2,167,351 and, indeed, many times more eifective than thecorresponding l-methyl compounds, even meperidine itself. For example,my ethyl 4-phenyl-1(3-phenyl-2-propenyl)piperidine-4-carboxylate as itshydrochloride salt, when measured as hereinbefore mentioned, isapproximately twenty-eight times more effective an analgesic asmeperidine hydrochloride, or thus having an analgesic activityapproximately one hundred and twelve times that of the correspondingknown l-benzyl homolog. In addition to having this high analgesicactivity, my compounds have a relatively low toxicity; for example, saidethyl 4-phenyl-1- 3 -pheny1-2-prop enyl pip eridine-4-carb oxylatehydrochloride is only about twice as toxic [intravenous toxicity inmice'when measured by a procedure similar to that described by Hoppe etal., J. Pharm. and Exp. Therap. 95, 502 (1949)] as meperidinehydochloride, so that its therapeutic index compared with meperidinehydrochlo ride is approximately fourteen.

A preferred subgenera of my compounds are the lower alkyl4-pheny1-1-(3-phenyl-propenyl and -propynyl)- piperidine-4-carboxylates,which in free base form have the formula Cell; C 0 O-(lower alkyl) Theseunsaturated phenyl-propenyl and phenyl-propynyl compounds, in additionto being useful as analgesic agents, are also useful as intermediatessince they can be hydrogenated catalytically to produce the relatedlower alkyl 4- phenyl- 1- (3- phenylpropyl)piperidine-4- carboxylates,which are disclosed and claimed in my copending application, Serial No.533,889, filed September 12, 1955. Preferred embodiments of thisinvention are the lower alkyl4-phenyl-1-(3-phenyl-2-propenyl)piperidine-4-carboxylates which havebeen shown by the rat thermal stimulus method to have particularly highanalgesic activity.

The lower alkyl 4-phenyl-1-(3-phenyl-propenyl and-propynyl)piperidinel-carboxylates are prepared by reacting a loweralkyl 4-phenylpiperidine-4-carboxylate with a 3-phenyl-propenylatingagent or a 3-phenyl-propynylating agent, said agents being preferably3-phenylpropenyl or 3-phenyl-propynyl esters of a strong inorganic acidor an organic sulfonic acid, said ester having the formula, C H YAn,where An is an anion of a strong inorganic acid or an organic sulfonicacid, as illustrated hereinabove, and Y is an unsaturated aliphaticdivalent hydrocarbon radical having three carbon atoms, as illustratedhereinabove. This reaction is carried out by heating the lower alkyl4-phenylpiperidine-4-carboxylate with the 3-phenyl-propenyl or3-phenyl-propynyl ester in the presence or absence of a suitablesolvent, but preferably in the presence of a solvent such as a loweralkanol. Specific illustrations of the preparation of these unsaturatedcompounds are: the preparation of ethyl 4- phenyl 1 (3 phenyl 2propenyl)piperidine -4 -carboxlate by heating ethyl4-p'henylpiperdine-4-carboxy1ate with 3-phenyl-2-propfenyl bromide; andthe preparation of .ethyl 4-phenyl-1-(3-phenyl-2-propynyl)piperidine-4-carboxylate 'by heating ethyl 4 -phenylpiperidine-4-car- .bogg-ylatewith 3 phe'nyl-2-propynyl bromide. These preparations were carried outpreferably in refluxing n'-buta-- nol'with stirringin the presence of analkaline agent such-,as sodium carbonate to neutralize the hydrogenhalide formed by the reaction. The products are isolated in free baseform or in the form of their acid addition; salts.Catalytichydrogenation of ethyl 4-phenyll-(3phenylQ-propenyl)piperidinet-carboxylate ethyl 4-phenyl-l(3-phenyl-2-propynyl) piperidinel-carboxylate using,r espe,ctively, onefor two molar equivalents of hydrogen yields, in' each instanceiethyl4-phenyl1 (3ephenylpropylipiperidine-4-carboXylate.

, My new lower alkyl -4-phenyl-1(3-phenyl-propenyl and-propynyl-)piperidine-4-carboxylates are useful inlthe free. base formor in the form'of acid addition salts, and

' these salts are within the purview ofpthe invention. The acids :whichcan be used to prepare acid addition vsalts are preferably those whichproduce, when combined with thefree base, salts whose anions arerelatively. innocuous to the animal organism in therapeutic doses'ofthe'salts, so that the beneficialphysiological properties inherent inthefree base are not'vitiated by side efiects ascribable 'to the anions.In practicing my invention, I found it i Following the above procedurebut using methyl 4- phenylpiperidine 4-carboxylate, isopropyl4-phenylpiperidine-4-carboxylate, n-butyl4-phenylpiperidine-4-carboxylate, or n-hexyl4-phenylpiperidine-4-carboxylate in place of ethyl4-phenylpiperjdine-4-carboxyl ate,=there is obtained in the form of thehydrochlorideraddition salt the following respective compounds: methyl4-phenyl-l- (3-phenyl-2-propenyl)piperidine-4-carboxylate, isopropylconvenient to employ the hydrochloride salt.. However,

V The following examples will further illustrate the in vention without,however, :Ilirniting it thereto.

' EXAMPLE :1 Lower alkyl 4-phenyl-1-(3-phenyl-propenyl)piperidine-I-carboxylate acid addition salts The preparation of these compounds isillustrated'by the following synthesis of ethyl 4-'phenyl-1'-(3phenyl-2-*propenyl)piperidine-4-carboxylate hydrochloride: A mix- C (three $150.ml. portions).

tureof 191g. of ethyl 4-phenylpiperidine-4-carboxylatehydrochloride,"14.0 g. of 3-phenyl-2-propenyl bromide (cinnamylbromide), 100 ml. of n-butanol and g. of anhydrous sodium carbonate wasrefluxed with stirring for about twenty-three hours. The reactionmixture was allowed to: cool, treated with carbon dioxide, and theresulting cloudy solution filtered, yielding a solution of ethyl4-phenyl-1- 3 -phenyl-2-prop enyl) piperidine-4-car+ boxylate in freebase. form. Hydrogen chloride was bubbled into the filtrate "and etheradded; the resulting 5 solid was collected and. recrystallized once fromethanoh 4 phenyl 1 (3 7 phenyl 2 propenyl)piperidine 4 carboxylate,n-butyl 4-phenyl-l-(3-phenyl-2-propenyl)" piperidine 4 carboxylate, orn-hexyl 4 phenyl 1'- (3-' pheriyl-Z-propehyl)piperidine 4-carboxylate. V

Pharmacological evalution of ethyl 4-phenyl-1-(3- phenyl-Z-propenyl)piperidinel-carboxylate. V hydrochloride in aqueous solutionadministered intraperitoneally or subcutaneously by the Rat ThermalStimulus Method of Bassand Vander Brook [1. Am."Pharm. Assoc., Sci.

'Ed., 41, 569-570 (1952)] has shownfthat this compound is approximatelytwenty-eight times aszactive an analgesic as ethyl4-phenyl-'1amethylpiperidine 4rcarboxylatehydro} chloride; Thiscompound'was found to have an acute toxicity in mice of 1-6.7:11 mg. perkg. when admin-l isteredintravenouslyin aqueous solution. 1 7 EXAMPLE 27 Lower alkyl 4-phenyl-J-(3-phenyl-pr0penyl)- piperidine-4-carb0xylatespreparationof these compounds from the corre spending acid additionsalts described in Example l is illustratedbythe followingpreparationtofethyl 4-pl1 enyl- '1-(3-phenyl-2-propenyl)piperidine 41-carboxylate from hydrochloride salt; A suspension containing g. of Jethyl i -phenyl-1-'(3 phenyl 2 propenyl)piperidine-l car boxylatehydrochloride in 250 ml. of water'was .made

alkaline; with sodium hydroXideQsolution;andthe liberated basic product.was extracted with benzene The combined. benzene extractswere' washedwith water anda saturated aqueous solution of NaCl, and thenconcentrated in vacuo. 'The. a resulting clear oily product solidifiedand was taken up 7 1 in ether; .the ether solution was dried over.anhydrous calcium sulfate, filtered, and the filtrate concentrated todryness in vacuo to yield the solid product, ethyl 4- phenyl; 1 (3-phenyl- 2 propenyDpiperidine 4- carboxylat, M. P. 49.7-51.1" C. (corn).V Analysis.-Calcd. for ,C H' NO C. 79.10; H, 7.73. Found: C, 79.15; H,7.97. w i e EX L Lower alkyl 4.-phenyl-1-(3-phenyl-pr0pynyl)piperidirte4- carboxylates V The preparation of these compounds is illustrated bythe synthesisiof ethyl 4 phenyl '1 (3 phenyl 2-pro-' ether (the ethanolcontaining dilute hydrochloric acid) 7 and three times from watercontaining hydrochloric acid. The' resulting product, ethyl'4-phenyl-l-(3-phenyl-i2- propenyl)piperidine'4-carboxylatehydrochloride, melted at 2l1.2213.2 C. (com). a Analysisr calcd. for CH' NO HCl: -C, 71.59; H,

7.31; Cl, 9.19. Found: C, 71.32; H, 7.43;'Cl, 8.90.

The above-described preparation is also carried outjliquid'preparations, e.' -g., aqueous or aqueous-ethanol inenstruum, orin solid form, e. g, tablet or powder;

Thetabletjformulationcan be prepared'usin'g' conventionalxcipientsyand-the powder can be compounded in capsule using ethyl4ephenylpiperidine-4-carboxylate in freebase form and only one half asmuchgsodium carbonate. Alternatively, this preparation can be carriedout using other esters such as 3-phenyl-2-propenylpara-toluenesulfonate-or'iodide, in placeof 3-phenyl-2-p'ropenylbromidefi. Use' of S-phenyl-l-propenyl 'bromidein theabove procedure:inaplace. of :3-phenyl-2-propenyl bromide yields ethyl 4-phenyl-1-'(3phenyl1-propenyl)piperidine s 4 -carboxylateand its hydrochloride.

pynyl) piperidine 4-carboxy1at following the procedure given hereinabovein ;Example-1, using an equivalent; 7, quantity? of i3'-phenyl-2-propynyl bromide in place of 3- phenylQ-propenyl bromide.- Theresulting product can; ,be isolatedin free base form or in the form ofits hydrochlorideaddition salt. V r I p V f My lower alkyl 4 phenyl 1 (3phenyl-propenyl or propynyl)piperidineA-carboxylates can be formulatedin form. jTheseprparations can'be administered orally or,

in the-case of the aqueouspreparation s, intramuscularly orintravenously. Iv cl i 1.;A'compoundise ted m" h g up dfi fing b V cyl)'p p d ne-4=carbo; y1ate; and its acid a itio 2. A lower alkyl 4phenyl l (3 phenyl 2 propenyl)piperidine-4-carboxylate.

3. A lower alkyl4-phenyl-l-(3-phenyl-2-propynyl)piperidine-4-carboxylate.

4. An acid addition salt of a lower alkyl 4-phenyl-1-(3-phenyl-Z-propenyl)piperidine-4-carboxylate.

5. An acid addition salt of a lower alkyl 4-phenyl-l-(3-phenyI-Z-propynyl) pip eridine-4-carboxylate.

6. Ethyl 4-phenyl-l-(3-phenyl-2-propenyl)piperidine-4- carboxylate.

7. Ethyl 4-phenyl-l-(3-phenyl-2-propynyl)piperidine-4- carboxylate.

8. Ethyl 4-phenyl-l-(3-phenyl-2-propenyl)piperidine-4- carboxylatehydrochloride.

9. Ethyl 4-phenyl-l-(3-phenyl-2-propynyl)piperidine-4- carboxylatehydrochloride.

10. The process of preparing a compound having the formula CuHs C OO-(lower alkyl) C CHg CE: /CH2 where Y is selected from the groupconsisting of propenyl and propynyl radicals, which comprises reacting alower alkyl 4-phenylpiperidine-4-carboxylate with an ester having theformula where A11 is selected from the group consisting of anions of astrong inorganic acid and an organic sulfonic acid.

11. The process of preparing a lower alkyl 4-phenyl-1- (3 phenyl 2propenyl)piperidine-4-carboxylate which comprises heating a lower alkyl4-phenylpiperidine-4-carboxylate with a 3-phenyl-2-propenyl halide.

12. The process of preparing ethyl 4 phenyl 1 (3- phenyl 2propenyl)piperidine 4 carboxylate which comprises heating ethyl 4phenylpiperidine 4 carboxylate with 3 phenyl 2 propenyl bromide.

13. The process of preparing a lower alkyl 4 phenyl- 1 (3phenyl-Z-propynyl)piperidine-4-carboxylate which comprises heating alower alkyl 4-phenylpiperidine 4 carboxylate with a 3 phenyl 2 propynylhalide.

14. The process of preparing ethyl 4 phenyl 1 -(3- phenyl 2propynyl)piperidine 4 carboxylate which comprises heating ethyl4-phenylpiperidine-4-carboxylate with 3-phenyl-2-propynyl bromide.

Referenres Cited in the file of this patent UNITED STATES PATENTS UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 2,824,875February 25, 1958 Bill Elpern It is hereby certified that error appearsin the printed specification of the above numbered patent requiringcorrection and that the said Letters Patent should read as correctedbelow.

Column 1, line 27, for "resipratory" read respiratory line 51, for "notknown" read now known line 55, for "meperdine" read meperidine column 2,line 18, for 'hydochloride" read hydrochloride line '72, for "boxlate"read boxylate column 3, line 35, for "acid phosphate" read acidphosphate,

Signed and sealed this 22nd day of July 1958.

(SEAL) Attest:

KARL H, AXLINE ROBERT C. WATSON Commissioner of Patents AttestingOflicer

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A LOWER ALKYL 4 -PHENYL - 1 - (3 - PHENYL - PROPENYL)PIPERIDINE-4-CARBOXYLATE, A LOWERALKYL 4-PHENYL-1-(3-PHENYLPROPYNL)PIPERIDINE-4-CARBOXYLATE, AND ITS ACIDADDITION SALTS.
 10. THE PROCESS OF PREPARING A COMPOUND HAVING THEFORMULA